Depression is a devastating illness that has profound effects on our society. Although effective treatments have been available for over 35 years, approximately 30 percent of depressed patients are nonresponsive to available medications and the mechanism of action of antidepressant treatments (ADTs) remains largely known. Recent studies from our laboratory and other suggest that adaptations of the cAMP pathway could mediate the actions of ADTs. We have found that chronic administration of different types of ADTs, including norepinephrine (NE) and 5-HT selective reuptake inhibitors, increases the expression and function of the cAMP response element binding protein (CREB) in rat hippocampus. In addition, we have found that chronic ADTs increase the expression of brain derived neurotrophic factor (BDNF) in rat hippocampus, suggesting that it may be a target of CREB. The first specific aim of this Project is to test the hypothesis that CREB mediates the upregulation of BDNF in hippocampus using a combination of molecular and pharmacological tools. The second specific aim is to test the hypothesis that 5-HT receptors regulate CREB and BDNF. This is based on our finding that selective 5-HT reuptake inhibitors increase the expression of BDNF. Our preliminary studies demonstrate that expression of BDNF is differentially regulated by 5-HT2A, but not 5-HT1A, receptors in hippocampus and neocortex; this can be explained by the different electrophysiological effects of 5-HT2A receptors in these brain regions. The third specific aim of this Project is to test the hypothesis that upregulation of BDNF by ADTs results in regulation of the morphology and function of hippocampla neurons. Preliminary studies demonstrate that certain ADTs regulate growth-associated and cytoskeletal proteins and cause sprouting of neurons in hippocampus. The relevance of altered neuronal morphology and regulation of BDNF is highlighted by recent studies demonstrating that chronic stress causes atrophy of hippocampal neurons in rats and nonhuman primates and that the volume of hippocampus is decreased in some cases of depression. The proposed studies will utilized the collaborative expertise of our group, and will include Northern and Western blot, in situ hybridization, immunohistochemistry, and single cell labeling and recording, as well as a variety of mutant mice provided by the transgenic core facility. These studies outline a new area of research that will further our understanding of the molecular and cellular actions of ADTs, and could lead to more fast-acting and efficacious treatments for depression.